Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

From injury through healing, thrombin has several important functions in blood clotting, subsequent clot lysis, and tissue repair. These include edema, inflammation, cell recruitment, cellular releases, transformations, mitogenesis, and angiogenesis. Thrombin also participates in disease states, such as venous thrombosis, coronary thrombosis, stroke, and pulmonary emboli, among others and is implicated in atherosclerosis, the growth and metastasis of certain cancers, Alzheimer's disease, and perhaps other conditions. Thrombin must be continually generated to sustain normal and pathogenic processes. This is because of a variety of consumptive mechanisms. Unlike other activated factors in thrombotic and fibrinolytic pathways, and because thrombin promotes its own generation (feedback and cellular activation), thrombin is a primary target for therapeutics. Besides recombinant hirudins, Argatroban (Novastan) and Bivalirudin (Hirulog) are promising thrombin-directed inhibitors for antithrombotic intervention.
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PMID:Thrombin and antithrombotics. 957 30

Given the central role of thrombin in arterial thrombogenesis, most treatment strategies for acute coronary syndromes are aimed at inhibiting its generation or blocking its activity. Although heparin has been widely used, it has limitations in the setting of arterial thrombosis. These limitations reflect the inability of heparin to inactivate thrombin bound to fibrin, a major stimulus for thrombus growth. In addition, the anticoagulant response to heparin varies from patient to patient, and heparin is neutralized by platelet Factor IV, large quantities of which are released from platelets activated at sites of plaque rupture. Consequently, heparin requires careful laboratory monitoring to ensure an adequate anticoagulant effect. Direct thrombin inhibitors, such as hirudin and bivalirudin, overcome the limitations of heparin. These agents inhibit fibrin-bound thrombin, as well as fluid-phase thrombin, and produce a predictable anticoagulant response. Bivalirudin has both safety and potential efficacy advantages over hirudin. Bivalirudin appears to have a wider therapeutic window than hirudin, possibly because bivalirudin only transiently inhibits the active site of thrombin. The better safety profile of bivalirudin permits administration of higher doses, which may give it an efficacy advantage. Hirudin prevents thrombin from activating protein C, thereby suppressing this natural anticoagulant pathway. In contrast, bivalirudin may promote protein C activation by transiently inhibiting thrombin until it can be bound by thrombomodulin. Differences between bivalirudin and hirudin, as well as other direct thrombin inhibitors, highlight the pitfalls of considering all direct thrombin inhibitors to have equivalent risk-benefit profiles.
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PMID:Direct thrombin inhibitors for treatment of arterial thrombosis: potential differences between bivalirudin and hirudin. 980 87

Enhanced adjunctive pharmacotherapy for percutaneous coronary revascularization is evolving. New modifications to the original antithrombotic, antiplatelet combination of heparin and aspirin have become part of standard practice. Platelet glycoprotein (GP) IIb/IIIa receptor inhibitors have been shown to decrease the incidence of death or nonfatal myocardial infarction at 30 days by approximately 50%. However, there are continuing concerns with this class of agents, including bleeding complications, cost, and the inability to identify which patients are most likely to benefit from their use. Bivalirudin, a direct thrombin inhibitor capable of inactivating clot-bound thrombin, has demonstrated enhanced short-term efficacy with a significantly decreased incidence of bleeding compared with heparin in patients with acute coronary syndromes. These findings provided a basis for a new, large-scale trial-Comparison of Abciximab Complications with Hirulog [and Back-Up Abciximab] Events Trial (CACHET)-which compares primary abciximab plus aspirin and heparin with aspirin plus intraprocedural bivalirudin and ad hoc abciximab. All patients who are candidates for stenting will receive clopidogrel before coronary intervention, and if stenting is performed, maintenance clopidogrel for 30 days. The trial aims to evaluate improved anticoagulation with bivalirudin and preprocedural oral antiplatelet protection and the use of ad hoc abciximab as a basis for a practical, acceptable antithrombotic, antiplatelet strategy to improve outcomes in percutaneous coronary revascularization.
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PMID:Evolution of improved antithrombotic and antiplatelet agents: genesis of the Comparison of Abciximab Complications with Hirulog [and back-Up Abciximab] Events Trial (CACHET). 980 94

Antithrombin drugs represent a wide group of natural agents, recombinant agents equivalent to some of the naturally occurring proteins, and synthetic agents. This group of drugs is characterized by marked structural and functional heterogeneity. Several of these drugs are currently in various phases of development. Argatroban represents the first clinically approved antithrombin agent, which was made available in Japan several years ago. Two recombinant hirudin preparations, Revasc (Novartis) and Refludan (Aventis), are available for postsurgical DVT prophylaxis and alternate anticoagulant use in patients with heparin-induced thrombocytopenia. A synthetic antithrombin agent based on the combined structures of hirudin and antithrombin peptides, hirulog (Bivalirudin), is undergoing clinical trials in cardiovascular indications. Additional studies on the hirudins are being carried out to test their efficacy as surgical and interventional anticoagulants as replacements for heparin. However, the need for a proper antagonist is one of the limiting factors for the optimal development of hirudin in this indication. Several of the synthetic thrombin inhibitors are also being developed for oral use for the prophylaxis of DVT in surgical patients. Since the therapeutic index of thrombin inhibitors is narrower than that of heparin, this route may not be an optimal approach for the development of these agents. Despite several unresolved developmental issues, the thrombin inhibitors provide a useful alternative to heparin anticoagulation and may prove to be useful in validated clinical use.
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PMID:Antithrombin agents: the new class of anticoagulant and antithrombotic drugs. 1072 36

Bivalirudin (Angiomax, The Medicines Company) is a synthetic 20 amino acid peptide rationally designed on the basis of structural studies of hirudin, a naturally occurring anticoagulant. Bivalirudin represents a new class of anticoagulant drugs that directly inhibits thrombin, a key component in blood clot formation and extension. With its high binding affinity and specificity for thrombin, bivalirudin acts directly on thrombin, rather than via other clotting factors. The compound has a variety of potential uses as an alternative to heparin in the management of cardiovascular disease and related medical procedures i.e., unstable angina (UA), myocardial infarction (MI) and percutaneous transluminal coronary angioplasty (PTCA).
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PMID:Bivalirudin: a new generation antithrombotic drug. 1106 Jul 32

Although heparin is widely used to treat arterial thrombosis, it has limitations in this setting. These limitations reflect heparin's inability to inactivate fibrin-bound thrombin, a major stimulus for thrombus growth, and the fact that heparin is neutralized by platelet factor 4, large quantities of which are released from platelets at the site of plaque rupture. Heparin also has a propensity to bind non-specifically to other plasma proteins. Because plasma levels of these heparin-binding proteins vary from patient to patient, the anticoagulant response to heparin is unpredictable and careful laboratory monitoring is necessary to ensure that an adequate anticoagulant effect is achieved. Direct thrombin inhibitors, such as bivalirudin and hirudin, overcome many of the limitations of heparin. These agents inhibit fibrin-bound thrombin, as well as fluid-phase thrombin. Direct thrombin inhibitors also produce a more predictable anticoagulant response than heparin because they do not bind to plasma proteins and are not neutralized by platelet factor 4. Bivalirudin appears to have a wider therapeutic window than hirudin. Because this may permit administration of higher doses of bivalirudin, this agent may also have an efficacy advantage over hirudin. Differences observed between hirudin and bivalirudin demonstrate that not all direct thrombin inhibitors have the same risk-benefit profile.
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PMID:The mechanism of action of thrombin inhibitors. 1115 31

Bivalirudin is one of the first of a new class of anticoagulants known as direct thrombin inhibitors. These drugs are able to overcome many of the shortcomings of traditional heparin anticoagulation by virtue of this unique mechanism of action. Bivalirudin is a semisynthetic derivative of hirudin, a modified component of leech saliva. Hirudin has been plagued by bleeding complications, likely due to its high affinity for thrombin. Bivalirudin has lower thrombin affinity than hirudin and therefore is believed to be a much safer compound. Bivalirudin has been shown to be a very effective anticoagulant in laboratory models, though its clinical efficacy remains to be fully proven. Bivalirudin has been studied in the setting of coronary angioplasty, unstable angina, and acute myocardial infarction and has shown some promise in many of these settings, particularly in preventing complications of percutaneous coronary interventions. Bivalirudin has consistently shown less major bleeding compared with standard heparin, although limitations in study methodologies somewhat hinder an accurate interpretation of this finding. Larger-scale studies are indicated and are currently being performed, the results of which will more definitively define the role of bivalirudin for the treatment of cardiovascular disease.
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PMID:Bivalirudin: a new approach to anticoagulation. 1197 81

Heparin is a commonly used anticoagulant in patients with coronary artery disease but its use does not always result in low rates of ischaemic and bleeding events, so the search for new anticoagulants continues. Thrombin plays a key role in both thrombosis and haemostasis and direct thrombin inhibitors modelled on the hirudin molecule found in the saliva of the medicinal leech, Hirudo medicinalis, have recently been developed. To date, the only direct thrombin inhibitor shown to reduce both the ischaemic and the bleeding complications associated with percutaneous coronary intervention (PCI) is bivalirudin, which is approved for this indication in the US and New Zealand. This agent is currently being studied in patients undergoing PCI with or without glycoprotein IIb/IIIa inhibitors and stenting. Bivalirudin has been shown to significantly reduce the risk of reinfarction in patients with acute myocardial infarction (MI) treated with streptokinase, but its use for this indication is not approved in the US. It may also prove to be beneficial in patients with acute MI treated with other fibrinolytic regimens or with primary or facilitated PCI. Bivalirudin is suitable for use as an alternative to heparin in the majority of patients undergoing PCI and in patients receiving streptokinase for acute MI.
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PMID:Bivalirudin: an anticoagulant for acute coronary syndromes and coronary interventions. 1203 17

Much progress has been made in understanding and treating acute coronary syndromes. For patients undergoing percutaneous transluminal coronary angioplasty, anticoagulant therapy during the procedure must strike a balance between providing sufficient anticoagulation to prevent thrombus formation and ischemic complications while averting hemorrhagic complications. Bivalirudin, a thrombin-specific anticoagulant, is the only anticoagulant that reduces both ischemic and bleeding complications associated with percutaneous coronary intervention (PCI). Bivalirudin is easy to use, provides predictable anticoagulation, inactivates both free and clot-bound thrombin, and blocks thrombin-mediated platelet activation and aggregation. Drug-drug interaction studies have found no clinically relevant interactions between bivalirudin and ticlopidine, abciximab, tirofiban, or eptifibatide. Bivalirudin is well tolerated by patients who previously received low-molecular-weight heparin (LMWH), when LMWH is discontinued 8-14 hours before bivalirudin is started. Similarly, switching from heparin to bivalirudin at the time of PCI reduces both ischemic and bleeding events.
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PMID:Clinical pharmacology of bivalirudin. 1206 67

Acute coronary syndromes encompass a spectrum of conditions, including myocardial infarction and unstable angina. These syndromes are related to the formation and disruption of atherosclerotic plaque. Rupture of plaque leads to thrombin generation, fibrin deposition, and platelet aggregation, ultimately resulting in restriction of blood flow and ischemia of cardiac tissue. Percutaneous coronary intervention (PCI), including angioplasty and coronary stent placement, has been developed to open occluded arteries. The frequency with which these procedures are performed speaks to their largely successful outcomes. However, the mechanical manipulations of PCI result in additional plaque rupture and damage to the vessel wall, exposing subendothelial components to blood and resulting in the initiation of the clotting cascade and in platelet activation. Left unchecked, these intertwined processes lead to formation of arterial thrombi at the site of endothelial damage, and potentially to abrupt vessel closure or embolization of thrombi into the distal microcirculation. Thrombin plays a central role in thrombus formation and platelet activation, and its inhibition significantly reduces thrombus-related sequelae. Current antithrombotic strategies during PCI are based on the traditional indirect thrombin inhibitor heparin. Heparin has several limitations in efficacy and safety, due in part to its indirect mechanism of action. Bivalirudin, a direct thrombin inhibitor, offers significant improvement over heparin in the clinical outcomes and risks associated with PCI.
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PMID:The role of thrombin inhibition during percutaneous coronary intervention. 1206 71


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